Ranolazine inhibits shear sensitivity of endogenous Na+ current and spontaneous action potentials in HL-1 cells

Peter Strege, Arthur Beyder, Cheryl Bernard, Ruben Crespo-Diaz, Atta Behfar, Andre Terzic, Michael Ackerman, Gianrico Farrugia

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

NaV1.5 is a mechanosensitive voltage-gated Na+ channel encoded by the gene SCN5A , expressed in cardiac myocytes and required for phase 0 of the cardiac action potential (AP). In the cardiomyocyte, ranolazine inhibits depolarizing Na+ current and delayed rectifier (IKr) currents. Recently, ranolazine was also shown to be an inhibitor of NaV1.5 mechanosensitivity. Stretch also accelerates the firing frequency of the SA node, and fluid shear stress increases the beating rate of cultured cardiomyocytes in vitro. However, no cultured cell platform exists currently for examination of spontaneous electrical activity in response to mechanical stimulation. In the present study, flow of solution over atrial myocyte-derived HL-1 cultured cells was used to study shear stress mechanosensitivity of Na+ current and spontaneous, endogenous rhythmic action potentials. In voltage-clamped HL-1 cells, bath flow increased peak Na+ current by 14 ± 5%. In current-clamped cells, bath flow increased the frequency and decay rate of AP by 27 ± 12% and 18 ± 4%, respectively. Ranolazine blocked both responses to shear stress. This study suggests that cultured HL-1 cells are a viable in vitro model for detailed study of the effects of mechanical stimulation on spontaneous cardiac action potentials. Inhibition of the frequency and decay rate of action potentials in HL-1 cells are potential mechanisms behind the antiarrhythmic effect of ranolazine.

Original languageEnglish (US)
Pages (from-to)457-462
Number of pages6
JournalChannels
Volume6
Issue number6
DOIs
StatePublished - Jan 1 2012

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Keywords

  • Drugs
  • Electrophysiology
  • Ion channels
  • Mechano-sensitivity
  • Myocytes

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

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